Search Results (348)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved. Full article

Simultaneously inhibiting beta-amyloid protein (Aβ) aggregation and reducing metal ion overload in the brain is a promising strategy for treating Alzheimer’s disease (AD). Aloe emodin (AE) is one of the major components of the traditional Chinese medicine rhubarb. Based on its reported pharmacological effects and its structural affinity for metal ions, this study aims to explore the potential of AE in improving AD pathology. Through the injection of Aβ or copper-Aβ complex in the bilateral hippocampus of rats, we constructed two kinds of nontransgenic animal models. Behavioral tests were used to evaluate cognitive impairment, and the effects of AE on neuronal damage and Aβ deposition were measured via Nissl staining and immunohistochemistry. Furthermore, we detected copper content in the serum and brain tissues as well as some biochemical indexes of Aβ cascade pathology in the brain tissues of model rats to explore the mechanism of action. AE treatment decreased copper accumulation and regulated Aβ metabolism in the brain of model rats, thereby improving Aβ deposition, memory impairment, hippocampal nerve cell damage, and related biochemical indicators. AE ameliorated the AD pathology of the model rats by targeting copper-induced Aβ toxicity, revealing a mechanism of action by which AE may exhibit good clinical efficacy in treating AD. Full article

Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for Alzheimer’s disease (AD). Viral infection of neuronal cells can reproduce hallmark pathological features of AD, including intracellular beta-amyloid (Aβ) accumulation, tau hyperphosphorylation, and lysosomal dysfunction. However, the molecular mechanisms underlying these alterations remain unclear, partly due to limitations of existing experimental models. Here, we established both two-dimensional (2D) and three-dimensional (3D) LUHMES neuronal cultures—a human mesencephalic-derived neural cell line that differentiates rapidly into mature neurons—to investigate HSV-1-induced AD-associated markers. Our results demonstrate that HSV-1 infection induces key features of AD, including intracellular accumulation of Aβ peptides and hyperphosphorylation of tau protein. Moreover, we observed disruptions in the autophagy–lysosome pathway, characterized by increased LC3-II levels, reduced cathepsin activity, and impaired lysosomal burden. Notably, these AD-like alterations were reproduced in 3D LUHMES neuronal aggregates, confirming their susceptibility to productive HSV-1 infection. Collectively, these findings indicate that HSV-1 not only triggers AD-like neuropathological markers but also disrupts cellular clearance mechanisms that may contribute to neuronal dysfunction and degeneration. This study validates the 3D LUHMES system as a useful human neuronal model to study virus-induced neurodegeneration and its mechanistic links to AD pathology. Full article

Alzheimer’s disease (AD) is considered one of the leading causes of death in the United States, and there is no effective cure for it. Understanding the neuropathological mechanisms underlying AD is essential for identifying early, reliable biomarkers and developing effective therapies. In this paper, we report on a comprehensive multimodal study of AD pathology using the 5xFAD mouse model. We employed light-scattering techniques, Partial Wave Spectroscopy (PWS) and Inverse Participation Ratio (IPR), to detect nanoscale structural alterations in brain tissues, nuclear components, and mitochondria. To support the light-scattering experiments, behavior, and histopathological studies were conducted. These analyses revealed significant increases in structural heterogeneity and mass density fluctuations in the brains of 5xFAD mice compared with Non-transgenic controls. Behavioral assessment performed using the Novel Object Recognition test demonstrated memory impairment in 5xFAD mice, reflected by a reduced recognition index. Histopathological analysis further revealed increased amyloid beta plaques and microglia activation in the hippocampus and cortex of 5xFAD mice compared with Non-transgenic controls. An increase in structural disorder within brain tissues can be attributed to higher mass density fluctuations, likely arising from macromolecular rearrangement driven by amyloid beta aggregation and neuroinflammatory responses as the disease progresses. Our findings suggest that PWS and IPR-derived metrics provide sensitive biophysical indicators of early cellular and subcellular disruption, offering potential as quantitative biomarkers for the detection of AD. Full article

Alzheimer’s disease (AD) is characterized by the accumulation and aggregation of tau and amyloid-β (Aβ). The pathophysiology and progression of AD are facilitated by the neurotoxic effects of these aggregated proteins, resulting in neurodegeneration and memory loss. In this context, the interaction between tau and Aβ42 is considered, but the mechanism underlying their pathogenic interplay remains unclear. Here, we addressed this question by studying the aggregation of full-length, unmodified tau and Aβ42 at physiologically low concentrations using atomic force microscopy (AFM). AFM imaging and data analyses demonstrate an increase in tau aggregation in the presence of Aβ42, characterized by increased sizes and number of aggregates. Importantly, tau aggregation occurs without the need for phosphorylation or any other post-translational changes. The analysis of the data demonstrates that tau and Aβ42 form co-aggregates, with no visible accumulation of Aβ42 aggregates alone. Given that the catalysis of tau aggregation by Aβ42 is observed at physiological low nanomolar concentrations of Aβ42, the finding suggests that such aggregation catalysis of tau by Aβ42 can be a molecular mechanism underlying the pathological tau aggregation process associated with the onset and development of Alzheimer’s disease. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD), share pathologic mechanisms including oxidative stress, mitochondrial dysfunction, and protein aggregation. However, they differ in age of onset and clinical progression. Emerging evidence highlights primary cilia (PC) as a key regulator of neuronal aging and the progression of these diseases. Dysfunctional PC may impair key signaling pathways, such as Sonic Hedgehog (Shh) and Wnt, promote oxidative stress, mitochondrial damage, and epigenetic instability. PC may also influence intercellular communication by regulating the biogenesis of exosomes and modulating tunneling nanotube (TNT) formation, both of which propagate toxic proteins between neurons. Mechanistically, the regulation of ciliary length is disrupted in AD, which leads to ciliary dysfunction that interferes with signaling pathways and promotes the aggregation of amyloid-beta. This amyloid-beta is then propagated through TNTs and exosomes, spreading neuronal damage. In PD, the accumulation of alpha-synuclein (α-syn) also impairs cilia function, thereby compromising the cell’s response to oxidative stress. This results in the formation of abnormal TNTs and defective exosome-mediated clearance, ultimately contributing to neurodegeneration. Similarly, the mutant huntingtin protein aggregates within primary cilia in HD, morphologically disrupting them by obstructing intraflagellar transport. Damaged cilia are also associated with increased TNT formation and the exosomal release of toxic proteins, which leads to mitochondrial and epigenetic instability, ultimately promoting neuronal aging. Together, targeting ciliary function and its downstream regulation of TNTs and exosomes may provide a novel approach for slowing or halting disease progression across neurodegenerative diseases. Full article

While genetics implicate a central role for dysregulated innate immunity in Alzheimer’s disease (AD), the contributions of peripheral myeloid cells, such as monocytes, have been largely overlooked in favor of microglia. Here, we investigate whether AD-associated loci, specifically rs3865444 in the CD33 locus and rs1057233 in the SPI1 locus, converge on shared functional pathways in monocytes in the context of amyloid-beta peptide 1-42 (Aβ1-42) as an immune stimulus. To do so, we isolated monocytes from peripheral blood mononuclear cells (PBMCs) from healthy individuals and exposed them to aggregated Aβ1-42. In this study, we identify functional convergence of the CD33 and SPI1 AD risk variants in the context of aggregated Aβ, both resulting in reduced phagocytosis and loss of surface TREM2 expression, demonstrating an interaction between genetics and environment to reduce myeloid cell fitness. These findings highlight that peripheral monocytes, like brain-resident microglia, are genetically and functionally linked to AD risk, underscoring their importance as accessible immune cells that contribute to disease susceptibility and progression. Full article

Alzheimer’s disease (AD) is a worldwide problem due to the lack of effective therapy and accurate methods for timely diagnosis. The complexity of AD’s pathophysiology complicates the development of effective therapeutic agents, as most drugs act on only one therapeutic target, bypassing others. The design and development of multifunctional agents capable of altering metal ion-induced abnormalities, oxidative stress, and toxic beta amyloid (Aβ) aggregates is of interest. Herein, we report the first boron dipyrromethene (BODIPY) based bifunctional copper chelator with clioquinol, BDP-CLQ, capable of both optical detection of Aβ fibrils and copper chelation, with multiple anti-AD properties. Foremost, BDP-CLQ demonstrated a 3-fold and 5-fold fluorescence increase at 650 nm and 565 nm in the presence of Aβ and effective copper chelation (pK_d = 16.6 ± 0.3). In addition, BDP-CLQ demonstrated a potent inhibition of Aβ aggregation, reduction in Aβ-induced stiffness of neuronal cells, and antioxidant activity. BDP-CLQ is the first BODIPY-based fluorescent probe with multiple anti-AD activities, as well as the first clioquinol-based probe capable of Aβ optical visualization. This study demonstrates the prospects of the development of clioquinol-based theranostic probes since this allows combining several promising anti-AD actions in a single molecule and developing multi-targeted drugs. Full article

Alzheimer’s disease is characterized by the accumulation of neurotoxic forms of amyloid-beta (Aβ) in the brain, leading to synaptic dysfunction, neuroinflammation, and neuronal death. The tetrapeptide HAEE crosses the blood–brain barrier (BBB), inhibits the formation of toxic Aβ oligomers, and reduces amyloid burden in vivo. However, the mechanisms of HAEE’s anti-amyloidogenic effect remained incompletely understood. In this study, we investigated the mechanism of HAEE-dependent Aβ clearance both in vitro and in vivo. Using ELISA, we assessed the HAEE effect on the levels of Aβ, IL-6, and TNFα in mouse brain tissue following intracerebroventricular administration. The mechanism of the anti-Aβ effect of HAEE was studied using primary brain cell cultures and a BBB transwell model through ELISA, flow cytometry, and microscopy. We showed that HAEE reduced Aβ level by 35% and IL-6 level by 40% in mouse brain tissue. HAEE enhanced Aβ clearance via LRP1- and PgP-dependent Aβ transport through the BBB and doubled the rate of Aβ degradation by microglia. In addition to inhibition of Aβ aggregation, HAEE dissolved already formed Aβ oligomers. The HAEE-induced decrease in IL-6 levels in the mouse brain was associated with reduced pro-inflammatory activation of microglia. Thus, HAEE’s effect against Aβ-related neuropathologies is realized through a decrease in the level of toxic Aβ oligomer and inhibition of neuroinflammation. Full article

Alzheimer’s (AD) and Parkinson’s (PD) diseases are the most prevalent neurodegenerative disorders (NDs), posing a growing global health burden due to the lack of effective therapies. Current treatments offer only limited symptomatic relief without preventing the progression of NDs. In the search for novel therapeutic strategies, peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a promising therapeutic target because mounting evidence suggests that PPARα activation can effectively modify key pathological mechanisms related to NDs, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired transcriptional regulation, processes leading to protein misfolding and aggregation. This review focuses on the potential therapeutic relevance of PPARα activation in AD and PD, discussing mainly insights from preclinical studies. Indicatively, gemfibrozil (PPARα agonist) markedly reduced the beta-amyloid burden, microgliosis, and astrogliosis in the hippocampus of 5xFAD mice and ameliorated their spatial learning and memory. Fenofibrate (PPARα agonist) reduced the depressive-like behavior and memory deficits in rotenone-lesioned rats developing Parkinsonism. It also restricted the depletion of striatal dopamine and protected their substantia nigra pars compacta from dopaminergic neuronal death and α-synuclein aggregation. Clinical trials gave disparate results, indicating either a benefit of fenofibrate in cognitive decline of AD patients or limited efficacy. The role of PPARα agonists in PD is less well established in human trials, which provided limited evidence of neuroprotection and reduced neuroinflammation. Although current findings are promising, they underscore the necessity of further rigorous clinical validation of the efficacy of various PPARα agonists in the retardation or even prevention of AD and PD symptomatology in both genders and the development of reliable biomarkers for the early assessment of the impact of PPARα agonists on NDs. The safety of these drugs in the elderly and their longitudinal effectiveness should also be evaluated. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease’s progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024–2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (−45.17 and −23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (−4.81 and −7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (−27.95 and −12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (−3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD. Full article

Extracellular particles (EPs), an umbrella term encompassing membrane-enclosed extracellular vesicles (EVs) and non-vesicular extracellular particles ([NVEPs], previously described as extracellular condensates [ECs]) contain a complex cargo of biomolecules, including DNA, RNA, proteins, and lipids, reflecting the physiological state of their cell of origin. Identifying proteins associated with EPs that regulate host responses to physiological and pathophysiological processes is of critical importance. Here, we report the findings of our study to gain insight into the proteins associated with NVEPs. We used samples from human semen, the rat brain, and the rhesus macaque (RM) brain and blood to assess the physical properties and proteome profiles of NVEPs from these specimens. The results show significant differences in the zeta potential, concentration, and size of NVEPs across different species. We identified 938, 51, and 509 total proteins from NVEPs isolated from rat brain tissues, RM blood, and human seminal plasma, respectively. The species-specific protein networks show distinct biological themes, while the species-conserved protein interactome was identified with six proteins (ALB, CST3, FIBA/FGA, GSTP1, PLMN/PLG, PPIA) associated with NVEPs in all samples. The six NVEP-associated proteins are prone to aggregation and formation of wide, insoluble, unbranched filaments with a cross-beta sheet quaternary structure, such as amyloid fibrils. Protein-to-function analysis indicates that the six identified proteins are linked to the release of dopamine, immune-mediated inflammatory disease, replication of RNA viruses, HIV-HCV co-infection, and inflammation. These interesting findings have created an opportunity to evaluate NVEPs for their potential use as biomarkers of health and disease. Additional in-depth studies are needed to clarify when and how these proteins sustain their physiological role or transition to pathogenic roles. Full article

Alzheimer’s disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (Aβ) peptides which have undergone fibrillogenesis to form insoluble Aβ fibrils (fAβ) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fAβ to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fAβ structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fAβ with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fAβ with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations. Full article

The development of positron emission tomography (PET) tracers targeting α-synuclein (α-syn) aggregates is critical for the early diagnosis, differential classification, and therapeutic monitoring of synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Despite recent advances, challenges including the low abundance of α-syn aggregates (10–50× lower than amyloid-beta (Aβ) or Tau), structural heterogeneity (e.g., flat fibrils in PD vs. cylindrical forms in DLB), co-pathology with Aβ/Tau, and poor metabolic stability have hindered PET tracer development for this target. To optimize our previously reported pyridothiophene-based radiotracer, [¹⁸F]asyn-44, we present the synthesis and evaluation of novel S,N-heterocyclic scaffold derivatives for α-syn. A library of 49 compounds was synthesized, with 8 potent derivatives (LMD-006, LMD-022, LMD-029, LMD-044, LMD-045, LMD-046, LMD-051, and LMD-052) demonstrating equilibrium inhibition constants (K_i) of 6–16 nM in PD brain homogenates, all of which are amenable for radiolabeling with fluorine-18. This work advances the molecular toolkit for synucleinopathies and provides a roadmap for overcoming barriers in PET tracer development, with lead compounds that can be considered for biomarker-guided clinical trials and targeted therapies. Full article